Device for neuroprosthetics with autonomous tunable actuators

ABSTRACT

A microelectromechanical device and method for neuroprosthetics comprises microactuators and microelectrodes. The microelectrodes are to be positioned in a nerve bundle and bonded with the microactuators through an interconnect. The position of each of the microactuators can be individually tuned through control signals so that the microelectrodes are implanted at desired positions in the nerve bundle. The control signals are transmitted to the microactuators and generated with a open-loop or closed-loop control scheme that uses signals acquired by the microelectrodes from the nerve bundle as feedback.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a non-provisional and claims the benefit of U.S. Prov. Pat. App. Ser. No. 62/151,316, having the same title, filed Apr. 22, 2015, and incorporated fully herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under R01 NS055312 and R21 NS084492 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

Devices for neural prosthetics are required to interact with neural tissue of the patient. Emerging prosthetic devices for the central and peripheral nervous system require interfaces that can stimulate or sense targeted neurons with high precision to achieve very specific functional states of the end-target organ. However, current neural interface and neuromodulation technologies lack the required stability and specificity to target specific sensory or motor neurons within a nerve bundle. These two attributes—stability and specificity—remain as the key challenges in developing chronic neural prosthetic technologies for central and peripheral nervous systems.

It would be desirable to have a device that can autonomously and precisely tune the position of the actuators of the neural prostheses to target a specific neuron in a nerve bundle.

SUMMARY

The present disclosure overcomes the aforementioned drawbacks by providing a microelectromechanical system (MEMS) device and method for neuroprosthetics comprising tunable microactuators and microelectrodes. The microelectrodes may be positioned in a nerve bundle and microbonded with the microactuators through an interconnect. The position of each of the microactuators can be individually tuned through control signals so that the microelectrodes are implanted at desired positions in the nerve bundle. The control signals are transmitted to the microactuators and generated with a closed-loop control scheme that uses signals acquired by the microelectrodes from the nerve bundle as feedback.

The device and method may further comprise a wireless telemetry where the wireless telemetry transmits recorded neurophysiologic signals acquired by the microelectrodes, micro-stimulation signals to the microelectrodes, and control signals of the microactuators. The wireless telemetry may communicate with the MEMS device through an interconnect or wirelessly. In one configuration, the interconnect is made of parylene polymer (poly para-xylylene) or polyimide, and connected via controlled collapse chip connection (“flip-chip”) onto the MEMS device.

In one configuration, the MEMS device is used for blocking neural motor signals when the frequency of microstimulation signals is more than 1000 Hz.

The foregoing and other advantages of the invention will appear from the following description. In the description, reference is made to the accompanying drawings which form a part hereof, and in which there is shown by way of illustration a preferred embodiment of the invention. Such embodiment does not necessarily represent the full scope of the invention, however, and reference is made therefore to the claims and herein for interpreting the scope of the invention.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A is a top view of a MEMS device configured in accordance with the present application;

FIG. 1B is a top partial view of a MEMS chip of the MEMS device illustrated in FIG. 1A;

FIG. 1C is an enlarged partial view of the MEMS chip illustrated in FIG. 1B;

FIG. 1D is a top view of the MEMS device illustrated in FIG. 1A and other wire-bonding packages, with insets A-C showing increased resolution of components of the MEMS device;

FIG. 2A is a top view of the microbonding between tunable microactuators and conventional microelectrodes of the MEMS device;

FIG. 2B is an enlarged view of an interconnect;

FIG. 3 is a diagram of a closed-loop control scheme of the MEMS device;

FIG. 4 is a cross-sectional perspective view of a nerve bundle showing microelectrodes of the MEMS device implanted into the nerve bundle;

FIG. 5A is a left perspective view of a MEMS device interfacing with a nerve bundle;

FIG. 5B is a cross-sectional view of the MEMS device of FIG. 5A showing microelectrodes interfacing with the nerve bundle and other components of the MEMS device;

FIG. 5C is an exploded left perspective view of the MEMS device of FIG. 5A;

FIG. 6 is a schematic diagram of a plurality of MEMS devices implanted to control a bladder;

FIG. 7 is a flowchart of an example method implemented in accordance with the present application to precisely tune the positions of microelectrodes in a nerve bundle; and

FIG. 8 illustrates a nanoelectrode.

DETAILED DESCRIPTION

The present application discloses a microelectromechanical (MEMS) device where the position of microelectrodes can be precisely tuned and therefore end-organ functional states can be reliably achieved or detected. This is to solve the drawbacks of other implantable technologies in neuroprosthetics. One of such drawbacks is that implantable neuroprostheses cannot be tuned to target specific motor or sensory neurons in the nerve bundle and, as a result, cannot be used to reliably achieve or detect end-organ functional states, especially in chronic conditions.

The MEMS device disclosed in the present application can precisely interface with targeted motor or sensory neurons in a nerve fiber. The MEMS device has three major features: (i) MEMS microactuators cause sensors, such as microelectrodes or nanorelectrodes, to move individually and precisely within nerve bundles; (ii) microscale or nanoscale bonding technique that provides electrical and mechanical bonding between the microactuators and microelectrodes to be implanted in nerve fibers; and (iii) a closed-loop autonomous control scheme for precisely positioning microelectrodes within nerve fibers to stimulate and achieve optimal end-organ functions or detect end-organ functional states. The closed-loop control scheme works in combination with the microactuators and the microelectrodes.

Referring now to FIG. 1A, a MEMS device 108 configured in accordance with the present application may include a flip-chip packaged MEMS chip 106. In one configuration, chip-scale interconnects of the device are parylene or polyimide leads flip-chipped onto the MEMS chip 106 using a packaging approach as disclosed in patent U.S. Pat. No. 8,653,642. FIG. 1D provides a size comparison of the flip-chipped MEMS device to typical wire-bonding packaging. The flip-chip packaging drastically decreases the chip sizes from 15 mm in width for a wire-bonding packaged chip 102, to 9 mm for a MEMS die flip-chipped on a glass substrate, and again to 3 mm in width for flip-chip packaged chip 106. As shown in inset (A) (FIG. 1A), the MEMS chip 106 may be connected with a control unit 111 through a flexible parylene-C transmission ribbon 110. The control unit 111 transmits recorded neurophysiologic signals acquired by microelectrodes 116, microstimulation signals to be relayed to the microelectrodes 116, and control signals of microactuators 112 to or from the MEMS chip 106. In certain embodiments, a nanoelectrode 801 (FIG. 8) is used to acquire recorded neurophysiologic signals.

The MEMS device 108 may be implemented with an implantable MEMS microdrive technology, such as a chevron-peg drive as disclosed in Electrothermal Microactuators with Peg Drive Improve Performance for Brain Implant Applications, J MICROELECTROMECH SYST. 21(5):1172-1186, Jul. 13, 2012, by the present Applicants, incorporated fully herein by reference. Inset B (FIG. 1B) shows in an enlarged view a portion of the MEMS chip 106, depicting a microactuator 112 and a microbonded microelectrode 116 attached thereto. The microactuator 112 (shown in an enlarged view in inset C (FIG. 1C)) extends from an electrothermal strip 114 on the MEMS chip 106. The electrothermal strip 114 provides a voltage to the microactuator 112 to actuate it. The actuation moves the microelectrode 116, which is microbonded as described below.

The device 108 disclosed in the present application may use a microscale bonding technique for conductive mechanical interconnects. In one configuration, the microelectrode 116 includes a polysilicon microelectrode 118 attached to the microactuator 112 of the MEMS chip 106 and bonded to a conventional implant 122 (e.g., stainless steel or platinum-iridium microelectrode), with or without an insulation, via a polyimide interconnect 120. The interconnects 120 are filled with conductive material, such as silver epoxy. In certain embodiments, these interconnects 120 combine the capabilities of conventional implant 122, which are directly implanted in the nerves, for stimulation and recording with the tunable capabilities of the MEMS microactuators 112. In other embodiments, conventional implant 122 indirectly interface with the nerve tissue when it is inserted in a glass micropipette, which is filled with electrolytes that may include payloads such as drugs, DNA plasmids, siRNAs, miRNAs or other gene constructs.

In certain embodiments, the mechanical interconnect 120 also allows the microelectrodes 116 to enter into a nerve bundle perpendicularly even when the MEMS microactuators 112 are parallel to the nerve bundle. Further, in some embodiments, the mechanical interconnect 120 enables microeletrods to enter into a nerve bundle at angles ranging from 0-180°. In turn, this allows a stable mounting of the MEMS device 108. Overall, the interconnects 120 improve the reach, directionality, and stimulation charge-injection ratios of the microactuators 112.

Referring now to FIG. 2A, another example MEMS chip 308 is provided to illustrate the microbonding. The chip 308 has three polysilicon thin film microelectrodes 302 each 50 μm wide. The conventional implant 306 has a diameter of 50 μm. The interconnects 304 in FIG. 2B are polyimide sleeves of 125 μm diameter filled with silver epoxy for conductive bond and microbond the polysilicon thin films from the MEMS chip 308 with the conventional implant 306.

Referring to FIG. 3, the device disclosed in the present application uses a closed-loop control scheme to tune microelectrode positions. Based on quality of neural signal feedback—such as signal-to-noise ratio (SNR), and signal shapes and amplitudes, the microelectrodes in the MEMS device can be independently moved to optimize neural signal quality. See FIG. 4 for an example closed-loop control scheme for autonomously navigating the microelectrodes in a nerve to optimize SNR of recordings. In one configuration, the MEMS device is used for bladder control. During the stimulation phase, the bladder pressure is used as feedback to move any one of the microelectrodes to optimize the efficacy of stimulation. Other signals, such as an electrical impedance, current consumption, mechanical force, stress, and strain generated in surrounding tissue can also be used as feedback.

In one configuration, a TBSI (Triangle Biomedical Systems International, Durham, N.C.) combo headstage is used for wireless telemetry of neural data and neural stimulation signals. The TBSI has five channels (two redundant) for wireless recording and two channels for wireless stimulation. An application-specific integrated circuit (ASIC) can also be used for wireless telemetry. Besides wireless telemetry of neural, power, and stimulation, an ASIC can also be used for wireless telemetry of the signals controlling the MEMS microactuators. Wireless telemetry can be configured in various ways. For instance, data is wirelessly telemetered to an external computer that runs the control scheme. The external computer or a microcontroller returns with trigger signals wirelessly to the TBSI device, which in turn generates the control signals for movement of the microelectrodes. In another example, the entire control scheme can be on an ASIC.

The telemetry device for the MEMS device can communicate with the MEMS device through interconnects or wirelessly.

In one configuration, the number of channels—or microelectrodes—can be scaled up to 6-12 microelectrode systems by integrating an implantable ASIC with the MEMS chip. This increase of channels marginally increases form factors of the chips.

FIG. 4 illustrates microelectrode implantation into a nerve 400. In one configuration, tunable MEMS microelectrodes 410 are slowly inserted into nerve bundles at locations that provide optimal motor control and sensing. In certain embodiments, the microelectrodes can move in steps of as small as about 6microns. In other embodiments, the microelectrodes can move in steps of about 2 μm to 10 μm. As described herein, “about” means a 10% different in measurement. The timing between successive steps can be as large as the user desires to achieve stable interfaces without mechanical disruptions to other neural interfaces in the vicinity. To help the microelectrodes 410 of the MEMS device penetrate a nerve 400 and its nerve fascicles (or bundles) 402, the microelectrodes 410 may be covered in guide tubes 412 of certain shape or material for easy penetration into the nerve 400 and fascicles 402. Once the guide tubes 412 penetrate the nerve 400 and fascicles 402, the microelectrodes 410 emerge from the guide tubes 412 and are in contact with neurons. The spacing between the microelectrodes 410 can be as small as 125 μm. The position of each of the MEMS microactuators, and in turn the position of each of the microelectrodes 410, can be independently tuned in micrometer-scale (e.g., 6 μm) increments within the nerve bundle for optimal performance in chronic conditions. In one configuration, three microelectrodes 410 with peg-drive are used for recording or stimulating.

Individual microelectrodes 410 of the MEMS device can also move in steps if neural interactions or neural prosthetics need to change in time. The stepping process allows the microelectrodes 410 to interface with axons of peripheral nerves at very slow stepping rates (<10 μm/s). This low rate allows individual microelectrodes 410 to move between axons and other components of peripheral nerves with damage minimized. This process can be validated on a larger nerve like the sciatic nerve before used on a smaller nerve like the pelvic nerve.

Referring now to FIGS. 5A-C, an example MEMS device is shown assembled around the nerve 400 of FIG. 4. An enclosure includes a top portion 502 and a bottom portion 504 that mate to enclose the nerve 400 within a channel 506 formed at the intersection of the portions 502, 504. The enclosure 500 may be made by 3D printing or another suitable manufacturing method. The enclosure 500 may be coated with a biocompatible silicone coat 508. A MEMS chip 510 may be held by the top portion 502 over the nerve 400. The microelectrodes 512 of the MEMS device extend from the MEMS chip 510 into guide tubes 514 that bend and guide the microelectrodes 512 into the nerve bundle as shown in FIG. 4. The guide tubes 514 allow the microelectrodes 512 parallel to the nerve 400 to penetrate the nerve 400. A polyimide or parylene transmission ribbon 516 can be flip-chipped onto the MEMS chip 510 and connects the MEMS chip 510 with a transceiver (i.e. control unit 111 of FIG. 1 or a telemetry device), such as a TBSI wireless headstage outside the animal. The MEMS device can also communicate wirelessly with a wireless telemetry device, such as an ASIC, without using the transmission ribbon 516.

Referring now to FIG. 6, a schematic diagram depicting an example MEMS device implanted to control bladder is provided. Example MEMS devices 602 are implanted on pelvic plexus 608. The MEMS devices 602 are secured onto the pelvic plexus 608 by cuffs 606.

The MEMS device can be used for recording neurophysiologic signals from a nerve or micro-stimulating a nerve. The MEMS array microelectrodes are positioned within nerve bundles at locations that provide optimal motor control and sensing. Current passing-through electrodes are used for stimulation when the current frequency is ˜20 Hz. When not stimulating or blocking, electrodes can detect local action potentials to monitor end-organ functional states.

Besides recording and stimulation, the MEMS microarrays can be used to block neural motor signals by using kilohertz frequency alternating current (KHFAC). Such current can be used to generate a local region of blocked axons, as demonstrated for intrafascicular electrodes in peripheral nerves. See PMID 19813186, D. Michael Ackermann, Jr. et al., Conduction Block of Peripheral Nerve Using High Frequency Alternating Currents Delivered Through an Intrafascicular Electrode, 41 MUSCLE & NERVE 117-19 (2010), available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947328/; PMID 20806397, Dowden B R et al., Muscle-Selective Block Using Intrafascicular High-Frequency Alternating Current, 42 MUSCLE & NERVE 339-47 (2010). Temporary DC stimulation can be used to alleviate potential onset responses to KHFAC. See PMID 25115572, Manfred Franke et al., Combine KHFAC+DC Nerve Block Without Onset or Reduced Nerve Conductivity After Block, 11 J. NEURAL ENGINEERING, Number 5, 2014.

Referring now to FIG. 7, a flowchart depicting an example method used to precisely tune the positions of microelectrodes in a nerve bundle is provided. In step 802, polysilicon microelectrodes of a MEMS device are microbonded with conventional implants through interconnects. In step 804, the microelectrodes are implanted into a nerve bundle in micrometer-scale steps. In step 806, the MEMS device receives neurophysiologic signals from the neural bundle sampled by the implanted microelectrodes. In step 808, control signals of microactuators are generated and transmitted to the microactuators. In step 810, the positions of the microactuators are tuned under the control of the control signals. In step 812, the neurophysiologic signals sampled by the microelectrodes in step 806 are used as feedback in a closed-loop control scheme to determine whether the microelectrodes are at the desired positions in the nerve bundle. If the microelectrodes are not at the desired positions, the neurophysiologic signals are used to update control signals for the microactuators, which in turn control the tuning of the positions of the microelectrodes; once the microelectrodes are at the desired positions, the loop ends.

This MEMS tunable microelectrode array is scalable and can provide a multi-modal interface used for visceral organ-specific targets or peripheral somatic pathways. Specifically, it can be used for controlling urinary bladder, controlling bronchial tone or detecting airway resistance or conductance in the bronchial tree, sensing oxygen in the carotid body, controlling catecholamine secretion in the adrenal medulla, or controlling upper extremity robots as peripheral nerve prostheses.

The device disclosed in the present application can be used in the areas of biomarker, biosignature, central nervous system therapeutics, cyber-physical system, medical diagnostics, bioaugmentation, brain and machine interface, gene delivery, drug delivery, implantable medical device, MEMS, neural implants, neural prostheses, neurostimulation and neuromodulation, point of care, prosthesis, and medical sensors.

EXAMPLES Experiments:

The following are experiments that can be used to test the device and method.

Experiment 1. Probe insertion tests in sciatic nerve can be done in acute experiments in 7 rodents. Rodent experiments lasting 7 days can be used to test the stability, signal quality, selectivity, and long-term performance of the integrated system in recording and stimulating axons in the sciatic nerve. The device can be powered with an external 500 mAh battery with an option for inductive powering.

Experiment 2. Target organ is bladder and the intervention point is preganglionic pelvic nerve. First start with five non-survival rat procedures. In these procedures, MEMS microarray placement and neuron identification can be established. Isoflurane anesthetized rats can be inserted with bladder and colon pressure catheters and their pelvic nerve can be exposed on one side. MEMS microarrays can be inserted in pelvic nerve fibers, followed by a bladder fill-void sequence. As needed, microarray probes depths can be adjusted in a step-wise fashion to optimize channel utility. At least three recording, stimulation, and blocking experiments should be performed, after successful stimulation parameters have been determined. Next, five survival experiments can be performed. MEMS microarray probes can be inserted in a way similar to that in the non-survival procedures. After a 7-day surgery recovery period, the animals can be lightly anesthetized and each of the recording, stimulation, and blocking experiments can be performed.

Other technical details in key areas:

The following are technical details in four key areas.

1. Probe insertion through epineurium. Peripheral nerves are different from cortical tissue. Inserting MEMS arrays into peripheral nerves while keeping the epineurium intact may be a challenge. The microelectrodes emerging from the guide tubes should be sharp to enable mechanical insertion through the epineurium using piezoelectric vibrations or linear force impulses. If needed, tapered ends for the guide tubes can be used in the package. The tapered ends can then guide the microelectrodes into the nerve bundle. Penetration through epineurium can be evaluated first in rat sciatic nerve experiments in Experiment 1 before pelvic nerve studies in Experiment 2. This way allows quick design modification and re-evaluation if needed.

2. Surgical attachment of the integrated package. The integrated package can be slightly larger in dimension than the pelvic nerve branches (see FIG. 6). The larger size has the potential to pull on the nerve. A fitted silicone cuff can be used to maintain stability of the package on the nerve and eliminate any relative motion between the package and the nerve. The cuff can first be evaluated with larger sciatic nerves in Experiment 1 before using it in smaller pelvic nerves in Experiment 2.

3. Identifying bladder axons of interest. The design of the MEMS arrays disclosed in the present application allows for individual probes to be positioned at optimal locations. Brief duration of a rat surgery may limit success rates in positioning probes at optimal locations within the rat pelvic nerve. This can be mitigated by using multiple probes for each function (recording, stimulation, or blocking) and first insert probes partially into the nerves (18-60 μm) before beginning bladder fill trials for neuron identification. After one or more bladder fill and neuron identification sequence, electrode probe positions can be adjusted in increments of 6 μm to optimize the afferent/efferent channel counts. The control approach used during the positioning is similar to that shown in FIG. 3.

The present invention has been described in terms of one or more preferred embodiments, and it should be appreciated that many equivalents, alternatives, variations, and modifications, aside from those expressly stated, are possible and within the scope of the invention. 

1. A microelectromechanical (MEMS) system for monitoring biological signals, the MEMS system comprising: at least one tunable microactuator; at least one sensor in signal communication with the at least one microactuator, wherein the at least one sensor is configured to be disposed in a biological tissue and to receive the biological signals generated by the biological tissue, the at least one sensor being at least one microsensor or at least one nanosensor; and a microcontroller in signal communication with the at least one microactuator and the at least one sensor, the microcontroller receiving the biological signals and, based on the biological signals, controlling the at least one microactuator to reposition the at least one sensor in microscale.
 2. The MEMS system of claim 1, wherein the biological tissue is a nerve bundle.
 3. The MEMS system of claim 1, wherein the at least one sensor is repositioned in an increment ranging from about 2 μm to about 10 μm.
 4. The MEMS system of claim 1, wherein a first sensor of the at least one sensor is a nanoelectrode.
 5. The MEMS system of claim 1, wherein a first sensor of the at least one sensor is a microelectrode.
 6. The MEMS system of claim 5, wherein the first sensor comprises a polysilicon microelectrode and a conventional implant, wherein the polysilicon microelectrode is microbonded with the conventional implant through an interconnect.
 7. The MEMS system of claim 6, wherein the conventional implant consists essentially of a metal that is selected from the group consisting of stainless steel, platinum, platinum-iridium, silver, silver-chloride, gold and tungsten.
 8. The MEMS system of claim 6, wherein the conventional implant comprises a material that is selected from the group consisting of optical fiber, light emitting diodes , organic light emitting diodes, and other microscale light sources emitting diodes.
 9. The MEMS system of claim 6, wherein the interconnect allows a perpendicular entry of the sensor into the biological tissue.
 10. The MEMS system of claim 6, wherein the interconnect enables the microelectrode to enter into the biological issue at an angle ranging from 0 to 180°.
 11. The MEMS system of claim 6, wherein the interconnect is conductive.
 12. The MEMS system of claim 1, wherein the biological signals are transmitted wirelessly by the at least one sensor to the microcontroller.
 13. The MEMS system of claim 1, further comprising one or more guide tubes each configured to dispose a corresponding sensor of the at least one sensor into the biological tissue.
 14. The MEMS system of claim 13, wherein the one or more guide tubes each comprise a tapered end that guides into the biological tissue the corresponding sensor disposed by the guide tube.
 15. The MEMS system of claim 1, wherein the microactuator is flip-chipped on a substrate.
 16. A method for positioning a microelectromechanical (MEMS) device within a nerve bundle of a subject, the method comprising: providing one or more sensors, each sensor comprising a first electrode formed from polysilicon in combination with a conventional implant; implanting the one or more sensors into the nerve bundle; receiving, at the one or more sensors, neurophysiologic and electrical impedance signals from the nerve bundle; and responsive to received signals comprising the neurophysiologic and electrical impedance signals, moving a distal end of the first electrode upwardly or downwardly within the nerve bundle to optimize the received signals;
 17. The method of claim 16, wherein moving the distal end of the first electrode comprises: generating one or more control signals using a closed-loop control scheme that uses the neurophysiological signals; and sending the one or more control signals to one or more microactuators in signal communication with the one or more sensors to adjust a position of the first electrode by the one or more microactuators so that the corresponding first electrodes of the one or more sensors are implanted at optimal positions in the nerve bundle.
 18. The method of claim 17, wherein moving the distal end of the first electrode further comprises utilizing other signals selected from the group consisting of the electrical impedance signal, a current consumption signal, a mechanical force signal, a stress signal, and a strain signal each generated in surrounding tissue of the nerve bundle as feedback.
 19. The method of claim 16, wherein the first electrode is a microelectrode.
 20. The method of claim 16, wherein the first electrode is a nanoelectrode. 